Stomach offers clue

Study links gut microbes to autism-like symptoms in mice

FILE - This is a Tuesday, Jan. 24, 2006 file photo of a laboratory mouse as it looks over the gloved hand of a technician at the Jackson Laboratory, in Bar Harbor, Maine. The lab ships more than two million mice a year to qualified researchers. Medical research in the U.K. is being jeopardized by activists who have persuaded transport companies to stop importing animals for scientific experiments, a former British science minister says. (AP Photo/Robert F. Bukaty, File) (CP)

Many physicians and parents report that their autistic children have unusually severe gastrointestinal problems such as chronic constipation or diarrhea. These observations have led some researchers to speculate that an ailing gut contributes to the disorder in some cases, but scientific data has been lacking. Now, a provocative study claims a probiotic treatment for gastrointestinal issues can reduce autism-like symptoms in mice and suggests that this treatment could work for humans, too.

The reported incidence of gut maladies in people with autism varies wildly between published studies -- from zero to more than 80 per cent -- making it difficult to establish just how commonly the two conditions go together, says principal investigator Sarkis Mazmanian, a microbiologist at the California Institute of Technology (Caltech). Overall, however, the evidence seems to point toward a connection. Last year, for example, a Centers for Disease Control and Prevention study of thousands of children with developmental disabilities found kids with autism were twice as likely as children with other types of disorders to have frequent diarrhea or colitis, an inflammation of the large intestine.

For many years, Mazmanian and his and colleagues have been studying the effects of a non-toxic strain of the bacterium Bacteroides fragilis on diseases such as Crohn's disease, which causes intestinal inflammation and allows potentially harmful substances that should pass out of the body to leak through junctions between cells that are normally tight. Although the researchers don't understand the mechanism, the bacterium appears to restore the damaged gut, possibly by helping close these gaps.

"The fact that we have an organism that repairs the gut makes it a very appealing" tool for testing whether gut abnormalities can contribute to autism, Mazmanian says. To explore that question, Mazmanian and colleagues at Caltech used a mouse model of autism that is thought to approximately recreate three of the disorder's hallmark deficits: lack of social interaction, decreased communication (mice normally emit ultrasonic, birdsong-like chirps) and repetitive behaviours such as compulsive grooming or burying marbles.

The first step of the experiment was to determine whether the mice showed signs of gastrointestinal inflammation or other gut abnormalities, says microbiologist Elaine Hsiao, a post-doctoral candidate at Caltech and lead author of the study. By the time the mice were three weeks old, the researchers found their intestines were indeed as leaky as those of mice that had been treated with a chemical that induces colitis. Next, the researchers tested whether they could reverse the damage by feeding the mice applesauce laced with B. fragilis for a week. A second group of autism-mimicking mice, as well as a group of healthy mice, ate applesauce that did not contain the bacteria. Then the group waited to see what effect the bacteria would have on the rodents' intestines.

"We didn't know what would happen; we were hoping the bacterium would survive in the gut," Hsiao says.

After three weeks, the team measured the levels of gut-derived molecules in the rodents' bloodstream and found the treatment had stopped up their intestinal leakage. Bacterial counts from rodents' droppings showed although B. fragilis did not establish lasting colonies in the mice, they did "shake up the community" of microorganisms, bringing it closer to that of the normal mice, Hsiao says.

After the treatment, the autism-mimicking mice also resembled their normal peers in two behavioral tests, the authors report last week in Cell. The animals no longer compulsively buried marbles in their cages and increased their ultrasonic squeaking to typical levels. They did not increase their social interactions, however, Hsiao says.

"It's really striking that any bacterial treatment -- even a transient one -- could have a lasting impact on behaviour," Hsiao says. The most interesting thing about the results, she says, was not the correction of the autistic symptoms in the mice, but the clues the study provided about how the gut's microbial population may affect the brain and behaviour. The researchers found levels of a substance called 4-ethylphenylsulfate that is produced by gut bacteria increased 46-fold in the mice with autistic symptoms, but returned to normal after treatment with B. fragilis. When the team isolated that chemical and injected it into healthy mice, the rodents showed increased anxiety, another autism-like symptom, she says. Although the substance did not provoke the symptoms seen in the previous experiment, Hsiao says the animals' altered response suggests the substance could play a role in the disorder. Hundreds of other metabolic byproducts also changed in quantity after B. fragilis was administered and could have an effect, she adds.

Although the findings are interesting, the study does not establish that the changing levels of microbes and the chemicals they produce caused any of the behavioural changes seen in the mice, says Emanuel DiCicco-Bloom, a neuroscientist at Rutgers University in New Jersey. "I'd want to know more about the mechanism" by which the bacteria altered behaviour in the mice before beginning to translate the findings to humans, he says.

The group also didn't investigate how the bacteria affect a normal animal, because the microbes were administered only to autistic mice, he says. It's possible B. fragilis could have a deleterious effect the study didn't detect, he says. Combined with the inherent difficulty of extrapolating findings about human autism from a mouse, he says, "I think this is less well-established than it appears."

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